Imipenem monohydrate is the N-formimidoyl derivative of thienamycin, and has the structural Formula I.
It is the first clinically available member of a new class of β-lactam antibiotics that possess the carbapenem ring system. Imipenem exhibits an extremely broad spectrum of activity against gram-positive and gram-negative aerobic and anaerobic species, which is partly due to its high stability in the presence of β-lactamases.
Imipenem was first disclosed in U.S. Pat. No. 4,194,047 and was obtained by lyophilization technique. The product obtained by lyophilization is found to be largely amorphous and stated to be thermodynamically unstable. The process also involves an initial purification through column chromatography using hydrophobic resins.
A thermodynamically stable crystalline monohydrate form of imipenem is disclosed in U.S. Pat. No. 4,260,543 which is obtained by crystallization of a lyophilized sample of imipenem. However, this process is not satisfactory on a commercial scale as it requires isolation of the product by column chromatography, lyophilization, followed by crystallization. Moreover, the prolonged process for isolation of the final product leads to degradation of imipenem, thus affecting the purity of the product.
U.S. Pat. No. 4,292,436 discloses crystalline imipenem by purifying the crude product by column chromatography. Further, Crocker et al. have reported in J. Pharm. Sci. 84, 226 (1995) that changes in lyophilization parameters result in varying degrees of crystallinity in the isolated imipenem samples. A variant method for preparing imipenem having a high degree of crystallinity by freeze crystallization process has been reported by Connolly et. al. in J. Pharm. Sci, 85, 174(1996). However, these processes are tedious, cumbersome and unsuitable for industrial use.